Tuesday, April 16, 2013

Schizophrenia is a brain disease: The fly brain man cometh

On 12th April, a BBC Radio 4 discussion included
a contributor suggesting first that schizophrenia is a brain disease, and
secondly that discoveries in the physiology of the fly brain could offer
insights into the origin of this ‘disease’.

[My colleague] forwarded me your email to him, which I feel
moved to reply to. I am copying in various colleagues who are as concerned as I
am about the naive biological reductionism that seems to be dominating media
discussions of mental health these days. Briefly, the problems with this view
when applied to 'schizophrenia' are:

(i) Schizophrenia is a meaningless construct

There is no syndrome of schizophrenia and nobody can agree
on who is schizophrenic. To my knowledge, no statistical study has ever
identified a cluster of symptoms that correspond to the Kraepelinian concept or
its subsequent revisions. Most recent studies have converged on a
multidimensional model that incorporates five dimensions of positive symptoms,
negative symptoms, cognitive dysfunction, depression and mania/excitability, or
even more complex structural models which encompass patients across the
psychosis spectrum (see Demjaha, A., et al. (2009). Combining dimensional and
categorical representation of psychosis: the way forward for DSM-V and ICD-11?
Psychological Medicine, 39(12), 1943-1955 and Reininghaus, U., Priebe, S.,
& Bentall, R. P. (in press). Testing the psychopathology of psychosis:
Evidence for a general psychosis dimension. Schizophrenia Bulletin, available
online). In recent field trials, the proposed DSM-V criteria for schizophrenia
generated a derisory kappa of 0.46, showing that clinicians working with a
precise definition of the disorder and following a diagnostic interview often
could not agree on who was schizophrenic and who was not (Regier, D. A., et
al(2013). DSM-5 field trials in the United States and Canada, Part II:
Test-retest reliability of selected categorical diagnoses. American Journal of
Psychiatry, 170, 59-70)!

(ii) Heritability coefficients are misleading

It is often forgotten that heritability coefficients are,
actually, fancy correlation coefficients. We all know, or should know, that
correlation does not necessarily prove causality. Heritability coefficients are
statements about populations and not individuals so that it is wildly
misleading to suggest that high heritability = mostly genetically caused (for a
detailed discussion of this, see Bentall, R. P. (2009). Doctoring the mind: Why
psychiatric treatments fail. London: Penguin.).

In fact, precisely because heritability coefficients are
correlations which attempt to parse up the variance in a trait to genetic and
environmental causes, low variance in the environment leads to inflation of
heritability. This is why, for example, IQ is highly heritable in middle class families
(where environmental variation is low) but very low in working class families
(where environmental variation is high) (Turkheimer, E., et al. (2003).
Socioeconomic status modifies heritability of IQ in young children.
Psychological Science, 14, 623-628). Also, heritability coefficients assume an
additive model of genes and environment, which is wildly implausible given what
we know know about how genes work. Again, assuming an additive model when there
are G x E interactions leads to massive inflation of heritability and an
underestimate of environmental effects (Dickins, W. T., & Flynn, J. R.
(2001). Heritability estimates versus large environmental effects: The IQ
paradox resolved. Psychological Review, 108, 346-369). This is probably why, as
you know, molecular estimates of heritability are generally much lower than
those based on the methods of classical genetics. The 'missing' heritability in
these studies is probably phantom heritability.

Incidentally, you will also know from the genetic studies
that you cite, that the consensus amongst geneticists is now that many common
alleles (perhaps hundreds) probably each confer a tiny risk of all kinds of
psychosis . Although some CNVs have much higher association with psychosis,
they account for only a small proportion of patients and are also associated
with intellectual disabilities and autism (Owen, M. J. (2012). Implications of
genetic findings for understanding schizophrenia. Schizophrenia Bulletin,
38(5), 904-907. doi: 10.1093/schbul/sbs103). This is further evidence, if ever
it was needed, that schizophrenia is a meaningless construct and confirms the
impossibility of devising a genetic test for the disorder.

(iii) There is massive evidence that environmental factors
are causal in severe mental illness

The implications of ii above are that you can't estimate
environmental influences from heritability estimates - you have to look for
them and measure them. Recent studies have pointed to a wide range of
environmental factors associated with psychosis. These include social
disadvantage, migration, living in cities and various forms of victimisation. I
attach a recent meta-analysis I conducted on the evidence linking childhood
adversity to psychosis (Varese, F., et al. (2012). Childhood adversities increase
the risk of psychosis: A meta-analysis of patient-control, prospective and
cross-sectional cohort studies. Schizophrenia Bulletin, 38, 661–671. doi:
10.1093/schbul/sbs050.) The bare odds ratio between childhood trauma was stable
across methodologies (retrospective/prospective) and came in at about 3, much
higher than any association with common alleles. More importantly, there is
evidence of a dose response effect, with Ors climbing to around 50 for children
who have been multiply traumatised. Reaction in the psychiatric community has
sometimes been bizarre, with convoluted attempts to explain away the data (see
a recent editorial I wrote about this, also attached).

(iv) Brain studies do not provide clear evidence of
neurodevelopmental disorder in psychosis

The evidence linking the basal ganglia to psychosis is far
from clear cut. The best evidence is from response to antipsychotics, but
recent studies suggest that only about 20% of patients show a genuine clinical
response (Marques, T. R., et al. (2011). The different trajectories of
antipsychotic response: antipsychotics versus placebo. Psychological Medicine,
41(07), 1481-1488). In any case, abnormal basal ganglia activity could just as
likely be attributed to environmental factors – animal studies show that
chronic victimisation leads to sensitisation of dopamine pathways in this part
of the brain (Selten, J.-P., & Cantor-Graae, E. (2005). Social defeat: Risk
factor for psychosis? British Journal of Psychiatry, 187, 101-102). Current
structural neuroimaging studies of psychosis are probably not to be trusted for
a variety of complex methodological reasons (Ioannidis, J. P. A. (2011). Excess
significance bias in the literature on brain volume abnormalities. Archives of
General Psychiatry, 68, 773-780), not least the emerging evidence that drugs
affect brain structure (Ho, B.-C.,et al. (2011). Long-term antipsychotic
treatment and brain volumes. Archives of General Psychiatry, 68, 128-137) but,
in any case, could also be the consequence of social and environmental factors
(Hoy, K., et al. (2011). Childhood trauma and hippocampal and amygdalar volumes
in first-episode psychosis. Schizophrenia Bulletin. doi: 10.1093/schbul/sbr085

(v) A narrow neurodevelopmental approach is damaging to
patients.

There is little evidence that the biological approach to
psychiatry is benefiting patients. Outcomes for patients suffering from
'schizophrenia' have not improved since the Victorian age and an increasing
number of people are disabled by psychiatric conditions. This is precisely the
opposite to what has happened in physical medicine, where genuine advances have
led to improved outcomes and reduced disability (see my Doctoring the Mind, and
also Whitaker, R. (2005). Anatomy of an epidemic: Psychiatric drugs and the astonishing
rise of mental illness in America. Ethical Human Psychology and Psychiatry, 7,
23-35). Just as importantly, although it is often assumed by doctors that
promoting a biological understanding of psychosis will reduce stigma, empirical
research provides strong evidence that the opposite is the case (Read, J., et
al. Acta Psychiatrica Scandinavica, 114, 303-318; Angermeyer, M. C., et al.
(2011). Biogenetic explanations and public acceptance of mental illness:
systematic review of population studies. British Journal of Psychiatry, 199,
367-372.)

The claim that biological research (on flies or whatever)
will one day lead to a cure for schizophrenia is a common rhetorical trick
designed to gain publicity and guarantee grant funding. I have no problem with
research on the CNS of flies, which seems valuable in its own right. But
linking flies to schizophrenia (whatever that is) is really about
self-promotion and is damaging to the interests of patients.

5 comments:

Professor Kinderman, thanks for sharing this. I've just recently watched another recent piece of work in the form of a TEDx talk talking about the same point being made about schizophrenia being a meaningless construct. Here is a link to that: Tedx Talk. I also discovered another website that's getting behind the schizophrenia movement: Schiz Life. Thanks for this information and keep up the good fight :)

My son recently got taught in school that schizophrenia was when you see and hear things and if you get it you have to take medication for life (although your schizophrenia will actually try to talk you out of it - and then you'll be in trouble!). So I hope you don't mind but I used the concepts behind this letter (and some of the stuff in it) to write a strong letter of complaint to the school.

My son was victim of a mental intriguing disorder called Schizophrenia unable to distinguish between fantasy and reality.And I have looked for solution, gave him Seroquel, Zyprexa and many medication but they were all worsened the situation, All hope was lost before I met a man who directed me to where I got my medication.It is a herbal medication, It is really good for Schizophrenia, SchizoAffective and Bipolar Disoder Personality treatment, It is better than those I have been using over the years, If you having such problem for advice and necessary solution, contact doson080@gmail.com

I decided to share this to help someone out there who is still held with schizophrenia. i suffered from chronic schizophrenia for 20 years and i have traveled round the world from one hospital to another neurologist and spent a lot of money, one day I took time to search internet which i found a lot of people thanking Dr. Nelson concerning the same problem and i discussed it with my wife and she said we should give a try so we order his product which i took for some months and am very much okay now.He is one of the Honest men out there. If you want to contact him on how to get his medicine or for info just reach him directly on drdavismartin62@gmail.com